Response: Plasma-derived or recombinant factor VIII products and inhibitors in previously untreated patients with severe hemophilia

We appreciate the letter by Calvez et al and we agree that analytic decisions affect the findings from studies. Calvez et al propose 2 explanations for the observed differences between the findings of the study by Goudemand et al,¹  the study by Chalmers et al,²  and our analyses of the Concerted Action on Neutralizing Antibodies in severe hemophilia A (CANAL) study.³  It was suggested that we found a smaller effect from recombinant products as opposed to plasma-derived products because we misclassified the exposure days of patients who received Beriate. Calvez et al proposed that Beriate should not have been included in the high–von Willebrand factor group. To examine this possibility, we repeated our analyses after excluding all 32 patients who had been treated with Beriate. In accordance with our previous findings, we found that patients on recombinant factor VIII products have the same risk as the patients on plasma-derived products with high–von Willebrand factor content (Table 1). Thus, Beriate did not explain the difference between our findings and the ones from Goudemand et al.¹ 

The other explanation concerned the fact that we had considered the factor VIII product as a time-varying variable, implying that the patients on plasma-derived products who switched to recombinant products during follow-up contribute their early exposure days to the plasma-derived group, and, immediately after the switch, they contribute exposure days to the recombinant product group. To evaluate this possibility, we excluded all postswitch exposure days and again repeated our analyses. The findings confirmed that the risk of inhibitors is not clearly increased in patients who received recombinant products as opposed to plasma-derived products with high–von Willebrand factor content (Table 1). In the table, we also present the findings of the CANAL study in the subgroup of patients who did not receive Beriate and whose exposure days are censored after switching from one product to another.

We have shown that the proposed explanations for differences between our study and the study by Goudemand et al¹  do not hold. Two other explanations could be the subject of future research: (i) other risk factors for inhibitors, such as intensity of treatment,⁴  may have confounded the study by Goudemand et al¹ ; (ii) some plasma-derived products indeed confer a lower risk of inhibitors. Yet, it seems unlikely that von Willebrand factor is a major player in this.